Myelodysplastic syndrome (MDS) is, at present, incurable preleukemic disease occurring most frequently among the elderly with about 14,000 new cases per year in the USA. About 30-40% of these cases progress to acute myeloid leukemia (AML). With an urgent need to improve therapy in this group, it is critical to generate effective modeling systems (including mouse models) for investigating the genetic lesions commonly observed in MDS and AML. However, the precise molecular mechanisms whereby genetic changes induce the progression of MDS to AML remain poorly understood. The proposed research focuses on an innovative mouse model for studying MDS progression and AML transformation through the somatic delivery of avian retroviruses that encode hyperactive KRAS and NRAS to transgenic mice. These mice have been engineered to bear the retroviral receptor, TVA, specifically within the hematopoietic stem cells that express an oncogene, SALL4B. We recently have identified this new oncogene and have discovered that overexpression of SALLB in mice exhibits MDS at age two months and, subsequently, displays AML transformation with a long latency. We hypothesize that additional mutations are required to activate a proliferative pathway, such as the RAS gene signaling pathway, to cause the SALL4B oncogene to mediate the transformation of MDS to AML. To test our hypothesis, RAS- encoding retroviruses will be delivered to mouse bone marrow where the SALL4B oncogene is overexpressed. Through our mouse model, we will characterize the cooperativity between hyperactive RAS with the SALL4B oncogene. The proposed studies will advance our understanding of the molecular events associated with MDS progression and AML transformation. An important outcome of our research with this innovative mouse model lies in the potential for developing effective target therapies for MDS thus improving the prognosis for patients facing this incurable disease. Such an advancement presents significant benefits to public health by reducing the high rate of mortality associated with MDS. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndrome (MDS) is, at present, incurable preleukemic disease occurring most frequently among the elderly with about 14,000 new cases per year in the USA. About 30-40% of these cases progress to acute myeloid leukemia (AML). With an urgent need to improve therapy in this group, it is critical to generate effective modeling systems (including mouse models) for investigating the genetic lesions commonly observed in MDS and AML. However, the precise molecular mechanisms whereby genetic changes induce the progression of MDS to AML remain poorly understood. The proposed research focuses on an innovative mouse model for studying MDS progression and AML transformation. An important outcome of our research with this innovative mouse model lies in the potential for developing effective target therapies for MDS thus improving the prognosis for patients facing this incurable disease. Such an advancement presents significant benefits to public health by reducing the high rate of mortality associated with MDS. [unreadable] [unreadable] [unreadable]